Slowing of fetal growth and elevated maternal serum sFLT1:PlGF are associated with early term spontaneous labor

Abstract

Background The physiological control of human parturition at term is unknown. Objective This study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor. Study Design We observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor. We estimated the probability of spontaneous delivery from 37 weeks of gestational age concerning (1) fetal growth between 20 and 36 weeks of gestational age and (2) the maternal serum soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio measured at approximately 36 weeks of gestational age. Data were analyzed using logistic regression and Cox regression. Results Fetal size at 36 weeks of gestational age was not independently associated with the timing of delivery at term. However, there was an inverse relationship between fetal growth between 20 weeks of gestational age and 36 weeks of gestational age and the probability of spontaneous labor at 37 to 38 weeks’ gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in abdominal circumference growth velocity, 0.60 [0.47–0.78]; P =.0001). This association was weaker at 39 to 40 weeks’ gestation (0.83 [0.74–0.93]; P =.0013), and there was no association at ≥41 weeks’ gestation. Very similar associations were observed for estimated fetal weight growth velocity. There was a positive relationship between soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio and the probability of spontaneous labor at 37 to 38 weeks’ gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio, 3.05 [2.32–4.02]; P <.0001). This association was weaker at 39 to 40 weeks’ gestation (1.46 [1.30–1.63]; P <.0001), and there was no association at ≥41 weeks’ gestation. Adjustment for maternal characteristics was without material effect on any of these associations. Conclusion Slowing of fetal growth and biomarkers of placental insufficiency were associated with an increased probability of early onset of spontaneous term labor. We speculated that progressive placental insufficiency may be a physiological phenomenon that occurs with advancing gestational age near and at term and promotes the initiation of labor.

Placental Syndromes—A New Paradigm in Perinatology

“…When the syncytiotrophoblast experiences lower oxygen supply and as it becomes hypoxic, more sFlt-1 is shed into the maternal circulation [ 82 ]. It was shown that PlGF, sFlt-1 and the sFlt-1/PlGF ratio were associated with spontaneous delivery [ 83 , 84 ]. Therefore, the associations between the angiogenetic biomarkers may play a role as a pregnancy biologic clock.…”

Routine first‐trimester pre‐eclampsia screening and risk of preterm birth

“…8,9,26 Finally, preterm labour is associated with an anti-angiogenic profile of an elevated sFlt-1-to-PlGF ratio, in common with PE and FGR. 10,11 The ASPRE trial did not find a significant difference in sPTB in the aspirin vs the placebo group. 12 Nevertheless, the results of an individual participant data meta-analysis including 17 RCT and 28,797 women showed a lower risk of sPTB at less than 37 weeks (RR 0.93, 95% CI 0.86-0.996) and less than 34 weeks (RR 0.86, 95% CI 0.76-0.99) in women assigned to antiplatelet treatment compared with placebo or no treatment.…”

“…Furthermore, approximately one-third of patients with sPTB have a failure of physiological transformation of the myometrial segments of the spiral arteries, which is typically associated with PE and FGR 8,9,26 . Finally, preterm labor is associated with an antiangiogenic profile of an elevated ratio of sFlt-1 to PlGF, in common with PE and FGR 10,11 .…”

“…8,9 Similarly, an imbalance in angiogenic factors with increased antiangiogenic elements such as soluble endoglin (sEng) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1) has also been associated with sPTB and early-term birth. 10,11 The ASPRE study introduced a first-trimester screening algorithm for preterm PE that combines maternal cardiovascular and placental factors to recognise women at higher risk of early uteroplacental dysfunction 12 . A subsequent clinical-effectiveness study demonstrated that the prophylactic treatment with low-dose aspirin in women at high risk of preterm PE could reduce the incidence of preterm PE by 80%.…”

“…Placental lesions consistent with maternal vascular hypoperfusion have been found in pregnancies complicated by preterm labor 8,9 . An imbalance of angiogenic factors, with increased levels of antiangiogenic elements such as soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) has also been associated with sPTB and early-term birth 10,11 .…”